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Clinical Trial
. 2023 May 1;9(5):683-691.
doi: 10.1001/jamaoncol.2022.7975.

Pembrolizumab Added to Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Relapsed or Refractory Classic Hodgkin Lymphoma: A Multi-institutional Phase 2 Investigator-Initiated Nonrandomized Clinical Trial

Locke J Bryan  1 , Carla Casulo  2 , Pamela B Allen  3 , Scott E Smith  4 , Hatice Savas  5 , Gary L Dillehay  5 , Reem Karmali  6 , Barbara Pro  6 , Kaitlyn L Kane  7 , Latifa A Bazzi  7 , Joan S Chmiel  7 , Brett A Palmer  6 , Jayesh Mehta  6 , Leo I Gordon  6 , Jane N Winter  6
Affiliations
Clinical Trial

Pembrolizumab Added to Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Relapsed or Refractory Classic Hodgkin Lymphoma: A Multi-institutional Phase 2 Investigator-Initiated Nonrandomized Clinical Trial

Locke J Bryan et al. JAMA Oncol. .

Abstract

Importance: To our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant.

Objective: To evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma.

Design, setting, and participants: A single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT.

Interventions: Two cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment.

Main outcomes and measures: The primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety.

Results: Forty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting.

Conclusions and relevance: Results suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant.

Trial registration: ClinicalTrials.gov Identifier: NCT03077828.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Casulo reported receiving grants from Genentech, Gilead, and Secura Bio outside the submitted work. Dr Allen reported receiving honoraria from Daiichi Sankyo, Kyowa Kirin, and BostonGene outside the submitted work. Dr Karmali reported receiving grants from Merck Sharp & Dohme LLC during the conduct of the study; grants from BeiGene, Takeda, Kite, and BMS; and personal fees from BeiGene, AstraZeneca, MorphoSys, Kite, BMS, Genentech/Roche, Calithera, EUSA Pharma, Janssen, and Karyopharm outside the submitted work. Dr Pro reported receiving grants from Merck Sharp & Dohme LLC outside the submitted work. Dr Bazzi reported receiving grants from the National Institutes of Health (NIH)/National Cancer Institute (NCI) to Northwestern University during the conduct of the study. Dr Chmiel reported receiving grants from NIH/NCI to Northwestern University for salary support during the conduct of the study. Dr Gordon reported receiving personal fees from Ono Pharmaceuticals, Kite Pharmaceuticals, Miltenyi, and BMS; receiving nonfinancial support from Janssen outside the submitted work; and cofounding Zylem, Inc, outside the submitted work. Dr Winter reported receiving grants from Merck Sharp & Dohme LLC, and NIH/NCI Cancer Center (P30 CA 060553) during the conduct of the study; and reported that her spouse received grants from Cellectis, Astellas, Gilead, Novartis, Daiichi Sankyo, and Rafael to the University of Chicago; personal fees from Novartis, Epizyme, CVS/Caremark, Ariad/Takeda, Servier, Jazz Pharma, Rigel Pharma, and Immunogen outside the submitted work; and royalties from UpToDate, Inc. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
AHSCT indicates autologous hematopoietic stem cell transplant; CMR, complete metabolic response; CR, complete response; ICE, ifosfamide, carboplatin, and etoposide; PD, progressive disease; PEM, pembrolizumab; PET2, 18F-fluorodeoxyglucose–positron emission tomography with computed tomography assessment after 2 cycles of combined PEM and ICE chemotherapy and 1 cycle of PEM monotherapy; PR, partial response; and TLI, total lymphoid irradiation.
Figure 2.
Figure 2.. Outcomes Data With Median Follow-up of 24 Months (Range, 0.5-35.4 Months)
A, Progression-free survival 2-year estimate was 87.2% (95% CI, 77.3%-98.3%). B, Overall survival 2-year estimate was 95.1% (95% CI, 88.8%-100%). Shaded areas indicate 95% CIs.
See this image and copyright information in PMC

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